Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenases (COX) 1 and 2. It is a prodrug which in the body is converted to the active COX inhibitor, sulindac sulfide. In recent years sulindac and other NSAIDS have been shown to possess anti-cancer activity and there has been considerable interest in how these compounds function to kill cancer cells. We have observed that colon, lung and skin cancer cells, after exposure to sulindac show enhanced sensitivity to oxidative damage resulting from exposure to agents such as tert-butylhydroperoxide and hydrogen peroxide, resulting in loss of viability. Under similar conditions normal cells do not show a decrease in viability and, in fact sulindac may provide normal cells some protection against oxidative damage. Metabolites of sulindac, such as sulindac sulfide and sulindac sulfone also show a similar effect in sensitizing cancer cells to oxidative damage. The results suggest that COX inhibition is not involved in the mechanism and the present proposal attempts to address why cancer cells are more sensitive to oxidative damage after treatment with sulindac. The proposed research plan will explore whether treatment of cancer cells with sulindac or one of its metabolites leads to increased cell killing by activation of an apoptotic cell death pathway. Furthermore, the proposed experiments will determine the mechanism of Sulindac cell killing by determining which apoptotic pathway is directly involved in this process; the activation of miotochondria or activation of the death receptor mediated apoptotic pathway. These studies should lead to a better understanding of why sulindac has anti-cancer activity and possibly offer the opportunity for development of more effective anti-cancer drugs. PHS 398/2590 (Rev. 09/04) Page 30 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Weissbach, Herbert The leading cause of death in the United States is now cancer. Nearly 20 million new cases of cancer have been diagnosed over the past 15 years with about 1.4 million new cases in 2005 alone. Sulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID). NSAIDS have been used as cancer chemopreventive agents but little is known about the molecular mechanism of NSAID-in the killing of cancer cells. We will contribute the understanding of the mechanism that lead to cancer cells death by the NSAID Sulindac and its derivatives. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page [unreadable] [unreadable] [unreadable]